Research from experimental animals, laboratory investigations, epidemiology and genetic forms of hypercholesterolemia indicate that elevated cholesterol is a major cause of coronary heart disease. The Framingham Heart Study also established that high blood cholesterol is a risk factor for coronary heart disease. Results of the Framingham study showed that the higher the cholesterol level, the greater the risk of suffering from coronary heart disease. On the other end of the spectrum, coronary heart disease is generally uncommon at total cholesterol levels below 150 milligrams per deciliter (mg/dL). A series of more recent trials of cholesterol lowering using statin drugs has demonstrated that lowering total cholesterol and low density lipoprotein (LDL) cholesterol reduces the chances of suffering a major coronary event, such as myocardial infarction, angina, or coronary artery procedures (e.g., angioplasty, bypass surgery). Grundy et al, Circulation, 110:227-239 (2004).
Total serum cholesterol contains three major classes of lipoproteins: about 60-70% LDL-cholesterol; about 20-30% high density lipoprotein (HDL) cholesterol; and about 10-15% very low density lipoprotein (VLDL) cholesterol. While LDL is the primary target for cholesterol lowering therapy, HDL and VLDL play a role in atherosclerosis.
The American Heart Association endorses the National Cholesterol Education Program (NCEP) guidelines for the detection of high cholesterol and the guidelines for healthy fasting lipoproteins. Total cholesterol levels of less than 200 mg/dL are desirable, while 240 mg/dL and above are high. HDL cholesterol levels of 60 mg/dL and above are considered protective against heart disease, while levels less than 40 mg/dL are a major risk factor for heart disease. LDL cholesterol levels of 129 mg/dL or less are near or at optimal, while 160 mg/dL or more are high. Triglyceride levels of less than 150 mg/dL are normal, while 200 mg/dL and above are high. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report, National Institutes of Health, NIH Publication No. 02-5215 (2002).
Current treatments to reduce elevated triglycerides, total cholesterol, and LDL-cholesterol in patients include small molecule oral monotherapy and combination therapy. The first drug of choice is generally an HMG CoA reductase inhibitor, i.e., statin. Exemplary statins include atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Another class of drugs is the bile ace sequestrants, such as colesevelam, cholestyramine, and colestipol. Yet another class of drugs is the fibrates, such as fenofibrate, clofibrate, and gemfibrozil. Other drugs used to treat high cholesterol include ezetimibe, nicotinic acid, and probucol. Several of these drugs are used in combination therapy, such as ADVICOR® (lovastatin and niacin by Abbott Laboratories); CADUET® (atorvastatin and amlodipine by Pfizer, Inc.); and VYTORIN™ (simvastatin and ezetimibe by Merck and Schering Plough).
Exendins are peptides that are found in the saliva of the Gila monster, a lizard endogenous to Arizona, and the Mexican Beaded Lizard. Exendin-3 is present in the saliva of Heloderma horridum, and exendin-4 is present in the saliva of Heloderma suspectum. Eng et al, J. Biol. Chem., 265:20259-62 (1990); Eng et al, J. Biol. Chem., 267:7402-05 (1992). Exendins have some amino acid sequence similarity to several members of the glucagon-like peptide (GLP) family. For example, exendin-4 as 53% sequence identity with glucagon-like peptide 1 (GLP-1). Göke et al, J. Biol. Chem., 268:19650-55 (1993). However, exendin-4 is transcribed from a distinct gene, not the Gila monster homolog of the mammalian proglucagon gene from which GLP-1 is expressed. Additionally, exendin-4 is not an analog of GLP-1. The structure of the synthetic exendin-4 peptide was not created by sequential modification of the structure of GLP-1. Nielsen et al, Current Opinion in Investigational Drugs, 4(4):401-405 (2003); Nielsen et al, Regulatory Peptides, 117:77-88 (2004).
Exendin-4 is a potent GLP-1 receptor agonist in vitro. The peptide also stimulates somatostatin release and inhibits gastrin release in isolated stomachs. Göke et al, J. Biol. Chem., 268:19650-55 (1993); Schepp et al, Eur. J. Pharmacol., 69:183-91 (1994); Eissele et al, Life Sci., 55:629-34 (1994). Exendin-3 and exendin-4 were found to be GLP-1 receptor agonists in stimulating cAMP production in, and amylase release from, pancreatic acinar cells. Malhotra et al, Regulatory Peptides, 41:149-56 (1992); Raufman et al, J. Biol. Chem., 267:21432-37 (1992); Singh et al, Regulatory Peptides, 53:47-59 (1994). The use of the insulinotropic activities of exendin-3 and exendin-4 for the treatment of diabetes mellitus and the prevention of hyperglycemia has been proposed. U.S. Pat. No. 5,424,286. Synthetic exendin-4, generically known as exenatide, is commercially available as BYETTA® (Amylin Pharmaceuticals, Inc. and Eli Lilly & Company). Sustained administration of exendins has been proposed. US Publication No. 2004/0053819.
The need exists for new and improved pharmaceutical compositions and formulations to reduce total cholesterol levels, LDL cholesterol levels, and triglyceride levels in patients in need thereof, to treat dyslipidemia, and atherosclerosis in patients in need thereof, and to reduce the risk of atherosclerosis, heart attacks and strokes in patients in need thereof. Pharmaceutical compositions and formulations that meet the needs of these patients are described herein.